Airways are protected from invading microorganisms by a highly efficient innate immune system. One defense mechanism available to the lung is the production of airway surface liquid and protective mucus, which ensnares viral and bacterial particles. This protective barrier coupled with the action of the ciliated airway cells, expels most foreign particles without engaging resident immune cells. In addition, most epithelial cells, including those of the airways, secrete microbicidal proteins into the biofilms that separate them from the external environment. One well-characterized family of antimicrobial peptides produced by mammals are the defensins. These are small cationic peptides capable of directly killing both gram positive and gram-negative bacteria as well as fungi and some enveloped viruses. They are also found in neutrophils where they are believed to be essential for non-oxidative killing of ingested microbes. The importance of this family of molecules is underscored by the fact that, not only have these genes been identified in all mammalian species studied, but it is likely that with more than 40 defensins in the human genome, there has been selection for redundancy in this system to ensure maximal protection against a broad spectrum of pathogens. More recently, evidence has emerged that suggest that these peptides might have a number of other important functions both in the innate immune response and in the transition of this response to one that engages lymphocytes. They may act both as natural antibiotics and as signaling molecules that activate host cells involved in immune defense and repair. We have identified a novel gene conserved between mouse and man, termed onzin, whose structure and sequence suggest that it is related to defensins. This gene is expressed by both the airway and the intestinal epithelia and is also expressed in high levels in neutrophils. In this application we test the hypothesis that onzin represents a novel defensive pathway that has a role in the innate immune response of the airways